Wednesday, December 23, 2009

The story lays out the history of how Merck addressed the problem it first faced with its new drug, alendronate (Fosamax): It seemed to be a breakthrough drug for treating osteoporosis and preventing hip and spine fractures in post-menopausal women; but sales were very slack.

So they brought in a marketing whiz named Jeremy Allen. And he did nothing less than invent the medical industry of bone mineral density (BMD) testing.

When Allen came along, there were very few BMD testing machines, because the machines were huge and expensive, and tests cost a lot and were not reimbursed by Medicare.

Allen's first response was to create an organization called the Bone Measurement Institute. Its board included 6 highly respected osteoporosis investigators. Its physical plant consisted of Allen's desk at Merck. Its funding was all Merck money.

Eventually Merck went so far as to buy out a medical device company to prove that it could make cheap BMD testing machines that would easily work in a physician's office, and do screening tests at reasonable cost. Merck claims that these smaller machines are effective. The device companies that make the bigger machines protested that the smaller machines were not accurate because they did not measure density at the hip and spine, but rather measured limb bone density, which research has shown change at different rates from the sites of the worst fractures. (Spiegel's story does not go this way, but please read John Abramson's excellent chapter on osteoporosis in his book, Overdo$ed America, explaining why drugs like Fosamax may make BMD numbers look great without doing anything really to reduce risk of fractures in most cases--especially in osteopenia.)

The Bone Measurement Institute eventually lobbied Congress to pass a law to get Medicare to pay for BMD scans. It now was profitable for docs to buy smaller machines for their offices and to offer the tests widely to patients.

Once patients began getting the tests wholesale, they saw that a paper printed out with three colored zones, green, red, and yellow. Green was normal and red was osteoporosis. Yellow was a thing called osteopenia which women had never heard of. When the term was formalized at a 1992 scientific meeting in Rome, it was seen simply as a name for the statistical condition of not-quite-osteoporosis, and not as a diagnosis, certainly not a disease that needed drug treatment. But the women who saw the yellow zone worried about their higher risk for fractures and started to demand that their doctors do something. Thus was born the widespread pharmaceutical therapy for osteopenia, which according to most research is essentially useless.

The dynamic at play here is the classic "disease mongering" as publicized by Ray Moynihan, the Australian journalist. It also highlights how often the best way to sell drugs is to sell screening instead.

Here's a good summation from Spiegel's article:

"I get a great sense of satisfaction that I was able to rejigger the marketplace so that women could be treated for osteoporosis before it got them," Allen says. "That was a good episode of my life."From Allen's perspective, by making a treatment for osteoporosis widely available, he helped save millions of lives.But [Richard] Mazess, from the Lunar Corp., [a maker of large BMD machines], doesn't see it that way. "He was complicit in a plot to misdiagnose American women," Mazess says of Allen.From Mazess' perspective, millions of women with osteopenia are now needlessly exposed to the risks of a medication that may not ultimately help them.The paradox of our health care system is that both of these men are probably right. That is, drug companies produce incredible drugs that can greatly relieve suffering. But one way they profit from those drugs is to extend their use to as many people as possible, which frequently means that medications are used in populations with milder and milder versions of a disease, so that the risks of medicating can come to outweigh the benefits.This morning my e-mail included no less than two notices about how physicians should be prescribing statin drugs for healthy people with normal cholesterol but with some heart-disease risk factors. Jeremy Allen at work behind the scenes again?

Monday, December 21, 2009

If that alphabet soup is perplexing, folks in the Office of the Inspector General, Department of Health and Human Services, commented on funding for physicians' continuing medical education (see below for cite, subscription required).

Lewis Morris, JD and Julie K. Taitsman, MD, JD include the obligatory Federal disclaimer that they do not speak on behalf of the OIG-DHHS. But they do remind us that their office wields a sizeable stick, having, for example, been involved along with Department of Justice in the recent criminal charges against Pfizer and Warner-Lambert over off-label promotion of Neurontin, which ended in a $430M settlement.

Morris and Taitsman begin by explaining that it is in the public interest to reduce the bias introduced into CME by commercial sponsorship, which now accounts for more than half the total costs of CME in the US. They stress that even if no specific drug is being shilled for at a CME program, commercial sponsorship still skews the content of CME toward drug treatment and the like, and away from equally important topics such as prevention and patient education. They also suggest that current guidelines that supposedly limit commercial interference in the choice of topics and speakers are relatively easy to get around.

They then list several strategies that might be employed to limit undesirable commercial bias in CME programming: avoid commercial funding entirely; insist that companies pay into a common funding pool and then have a neutral third party give CME programs grants from that pool on a competitive basis; accredit specific programs rather than CME providers so that individual programs come under closer scrutiny; and eliminate some types of CME providers who currently receive funding almost solely from commercial sources (medical education and communications companies). The authors' personal choice is for the pooled funding mechanism.

This paper is a good summary of the pitfalls in the current state of CME funding and gives us a hint as to where the Feds are going to be looking for future violations. As we saw in a previous post, others--specifically the IOM--have been less reticent about proposing the full elimination of commercial CME funding as the best option for the future: http://brodyhooked.blogspot.com/2009/05/iom-report-on-coi-yes-we-really-mean-it.html

Sunday, December 13, 2009

Back in September I blogged about an article and editorial in the Mayo Clinic Proceedings: (see Sept. 1 post-- for some reason I cannot get the copy/paste function to work here to provide the link!)

That post was very long and I went into laborious detail about both the article by Laurence J. Hirsch and the accompanying editorial by William L. Lanier, with some not very complimentary comments on each--so no point now repeating all that.

I did however want to note that the Chronicle of Higher Education has now reported on the resulting controversy, which apparently has continued to simmer. If you believe the Chronicle, the focus of the fracas has been on what I identified as the one apparently valid point in a rambling and illogical attack on Pharmascolds generally--the argument that we should be as suspicious about those who take a lot of money from Pharma foes as we are about those who are in the back pocket of Pharma.

The article provides an opportunity that eluded me at the time I first posted--to get the facts straight (or at least straighter) about the actual sums made by the two Pharmascolds singled out by Hirsch, Dr. Harlan M. Krumholz of Yale and Dr. David S. Egilman of Brown. According to Hirsch, as a result of their work for plaintiffs' lawyers suing drug and other companies, the former had pocketed a total of $300,000 and the latter as much as $25M. The sums according to the Chronicle are respectively $200,000 and $2M. (Yeah, I know, those pesky decimal points--funny how they jump around all over the place when you're not looking.) On the one hand it is a further point against Hirsch's article that he was so inaccurate in naming the proper sums. On the other hand, the sums are still substantial, and I agree that anyone who makes that sort of money as a result of being paid by X (whoever X might be) is at high risk for coming to the conclusion that X is a really fine institution and that the causes undertaken by X are especially noble causes; and that those who say nasty things about X are not nice people.

So, memo to the drug industry--if you don't want the likes of Drs. Krumholz and Egilman telling the world what they think of you and your research endeavors, then in the future, be more transparent in your activities, so that we can find out about you via some route besides the legal discovery process when you are sued big time for your misdeeds. That way we would not have to depend on plaintiffs' expert witnesses, who have been paid to do the sorry job of slogging through thousands of pages of internal e-mails and memos, to tell us what you have really been up to.

The company plans to charge $30,000 a month for this drug. Commonly used cancer drugs such as Avastin and Erbitux, for example, also accused of being over-priced, cost $8800 and $10,000 a month by comparison, respectively, says the Times. Moreover, the drug has been shown to shrink tumors but not to have any impact on mortality statistics.

The Times quotes James V. Caruso, chief commercial officer at Allos (whatever that is--do companies have non-commercial officers?), as defending the price by saying among other things that the cancer is so aggressive that no patient will be taking it for that many months, anyway.

So now we come to our lesson in PR strategies. If they ask you to defend the exhorbitant price of your cancer drug...

Do say:"Our treatment costs about the same as other treatments for other cancers.""Many millions of dollars were spent doing the research needed to develop this drug.""It's hard to put a price tag on hope as we continue to wage the war on cancer.""This particular cancer is very rare and so the only way to bring the drug to market was to increase the price per patient, much as we hated to do that."

Do not say:"Our drug is such a rotten drug, and people die so quickly with it, that they won't be around to spend that much money for very long anyway."

Hat tip also to PostScript and Jonas Hines for the original news and his own wry comment.

Wednesday, December 9, 2009

A set of articles posted yesterday on the BMJ website seems to have attracted next to no attention among the mainstream media, but raises a set of serious concerns about the integrity of medical research. Probably the most convenient entry point is via this editorial (subscription needed to access full text):http://www.bmj.com/cgi/content/extract/339/dec08_3/b5351

The key article in terms of the origin of the dispute is:http://www.bmj.com/cgi/content/full/339/dec07_2/b5106--which is an update of a Cochrane Collaboration review of the usefulness of oseltamivir (Tamiflu) for the prevention and treatment of influenza. The review (by Tom Jefferson and colleagues) differs from a 2005 review, that had viewed the drug as helpful for preventing serious complications of influenza. A Japanese investigator had alertly noted that the positive conclusions were apparently based on a single meta-analysis, but that the component studies on which the meta-analysis was based were not publicly available for review. So he questioned the earlier findings, and the Cochrane investigators decided that the only way they could respond to the question was by fully reconstructing the earlier meta-analysis.

Trying to summarize a very complex story (so complex that BMJ ended up teaming with Channel 4 News in the investigation), Jefferson et al. went back both to the company that sponsored all the studies (Roche, maker of Tamiflu) and to the named investigators who authored the reports of that research. The investigators did not have the original data and referred Jefferson et al. back to Roche. At least one purported investigator of a study said he never conducted that particular study. Roche first refused to provide any data, then provided partial summary data, and finally said they could not provide full data because a rival meta-analysis group was reviewing all the data. (Roche provided its side of the debate and it is printed in the same collection of BMJ articles.)

In the end, Jefferson et al. had to conclude that there are no available data to confirm the value of oseltamivir in preventing the complications of flu. Notice that governments around the world have spent billions of dollars stockpiling oseltamivir specifically under the impression that it is proven to prevent serious flu complications, and so represents a major public health response to pandemic influenza. (In yet another article, the BMJ concludes that observational studies supplied by Roche to supplement the published clinical trials also fail to demonstrate any more than a very small effect of the drug on preventing flu complications.) It now turns out that there is no well-established scientific basis for having spent all this money and having made this supposed investment in a public health response.

Fiona Godlee and Mike Clarke, the BMJ editorialists, are careful to note, "In being less then forthcoming with the raw data, Roche has done nothing wrong by current standards and even less by standards of 10 years ago. It has done exactly what the current system allows."

That leads them to the same conclusion that I proposed in HOOKED now nearly 3 years ago-- that we somehow need to unlink the machinery of medical research from commercial sponsorship of drug trials by individual drug companies, paying grants directly to individual investigators.

The BMJ series tends to support the comments of Roy Poses over at the Health Care Renewal blog (see http://hcrenewal.blogspot.com/2009/11/how-industry-views-research-it-sponsors.html), commenting in turn on an article published in last week's BMJ by Graf et al, proposing new standards for "good publication practice" on behalf the medical communications industry (the nice folks who bring you ghostwriting). Dr. Poses suggests that these guidelines provide a telling perspective on how the industry views research. From a typical academic-medical standpoint, a research study has a principal investigator or PI. The PI "owns" and accepts full accountability for the study. She gets the grant to fund the study; she oversees the conduct of the study and the analysis of the data; and she is chief author of the eventual publication. The buck stops with the PI. From an industry standpoint, no one owns and is accountable for the study. (The drug company may think it owns it but, as we saw with Roche, seems to run the other way when accountability is called for.) Who happens to be managing it at any point in time is a hireling who can be replaced at any instant, and the hireling who, say, authors the eventual paper may have no connection with the hireling who managed the study data collection, did the statistical analysis, or whatever. These are simply functions on an assembly line. What that means for the integrity of scientific research is something we can discuss.

Addendum 12/10: I noted in the original post that the mainstream media in the US did not seem to glom onto this story. I have since seen that AP and Yahoo did pick it up:http://news.yahoo.com/s/ap/20091208/ap_on_bi_ge/eu_med_tamiflu_evidenceThe news story adds the info that the WHO disputes the BMJ and says that it has a lot of faith in Tamiflu's value. There's a bit of conflict of interest here as the WHO has been one of the great promoters of the drug and has been behind a number of governments deciding to buy huge quantities for their national stockpiles. You can see how it would now be very embarrassing for them to have to admit that maybe the drug was oversold. If the WHO is so convinced that Tamiflu works, on what basis are they convinced; and why were the Cochrane reviewers unable to locate that evidence?

As a dutiful AAFP member I sent a letter to the President, Dr. Lori Heim, and the Executive Vice-President, Dr. Douglas Henley, raising the same concerns about conflict of interest and public trust in organized medicine that I did in my blog postings.

I have now received their reply. I have not yet formally resigned but the chances of my remaining an AAFP member do not look good.

There is no hint of any retreat from the stance taken by AAFP at the start, that this relationship is to be commended and not condemned--despite the fact that in the interim, the editor of one of the major family medicine journals, Dr. Jeff Susman of the Journal of Family Practice, wrote an editorial sharply critical of the AAFP's position (Susman J. Do things really go better with Coke? http://www.jfponline.com/Pages.asp?AID=8183&issue=December_2009&UID=).

Some samplings from the AAFP letter (which I assume was mostly a form letter sent to all members who complained): "As a long-time member..., you certainly must appreciate the fact that the AAFP has been managing relationships with outside funders successfully for many years. The Academy has then highest standards and rigorous rules...and rigorous firewalls are in place to assure the separation of editorial and policy decisions from funding considerations."

Comment: It is true that people like me have been very lax in the past. It seems the AAFP has been happily taking funds from a variety of commercial interests, and that Coke is only the latest in the series. Shame on us family docs for not objecting loudly before this. But past actions of a questionable nature certainly don't justify future actions even more discreditable.

"Your comparison with the AMA's Sunbeam situation is a false one...no product endorsements are expressed or implied...our board of directos has been kept fully informed at every stage of development...Our Board took the lessons of Sunbeam very seriously in our deliberations and took pains to avoid all those traps."

Comment--points well taken. In the various ways listed, the AAFP did not act exactly like the AMA. They do indeed seem to have learned all the lessons of Sunbeam except the final, and most important one: don't let the dollar signs blind you to how bad you're going to look when the deal becomes known to the wider public.

"The argument voiced by many is that even the appearance of a confliict means that a conflict exists and that it is irresolvable. The AAFP has never accepted this line of thinking. Conflicts need to be disclosed and then dealt with. Again, the AAFP has been very successful in disclosing and managing any potential conflicts..."

Comment: This is indeed a possible ethical position. It is, for reasons I discuss at length in HOOKED, a highly unsatisfactory one. It is also not the dominant position taken in the medical literature with regard to professional societies and their responsibilities to set the highest professional tone for their members. (For just one recent example see Rothman DJ, McDonald WJ, Berkowitz CD, et al. Professional medical associations and their relationships with industry: a proposal for controlling conflict of interest. JAMA 301:1367-1372, April 1, 2009.)

"In a world of complex relationships, when tensions are high and society is so polarized, there are two approaches an organization such as ours can take. One is a strategy of engagement, whereby we choose to work together with organizations different from the AAFP in areas of mutual interest to advance the greater good and build trust and influence to help change behavior. One example of this...involved the Coca-Cola Company a few years ago, when the Robert Wood Johnson Foundation, the William J. Clinton Foundation, and the American Beverage Association worked together to address the issue of suragy soft drinks sold in school vending machines. ... The other strategy is not to collaborate at all with such organizations..."

It was Arthur Schafer at Manitoba who first noted how quickly, in the minds of industry apologists today, "engagement" and "collaboration" somehow automatically segue into "taking a lot of money from." The AAFP leadership here poses an utterly false dichotomy. None of the AAFP members who are up in arms over the Coke deal are complaining because AAFP saw fit to engage with Coca-Cola.

Summary: The leadership of the AAFP appears to have elected to turn a blind eye toward the controversy sparked by the Coca-Cola deal and has apparently wrapped itself smugly in its assurance that it can do no wrong. This certainly leaves members like me in a bind, which sadly appears resolvable only by us parting company. If the AAFP decides that this means I am no longer willing to engage with them, I guess they will have to be of that mind.

Dr. Carlat received from a colleague a letter from a medical communications company, BlueSpark. There are two ways to interpret the letter to the colleague. Dr. Carlat favors the interpretation that the letter is an invitation to put one's name as guest author on an article that will be ghostwritten by BlueSpark. He contacted BlueSpark who, not surprisingly, vigorously denied this interpretation. They pointed to stipulations in the letter that required a phone conference between the colleague and their staffer; approval by the colleague of a detailed outline before a draft is completed; and final editing of the draft. They also added that if the role of their own writer met the official criteria for authorship of the medical journal editors' organization, then the staff writer's name would appear as a co-author.

To which Dr. Carlat replied that of course, in this day and age, no one is going to write a letter and say flat out, "Wanna put your name, for pay, on an article that somebody else actually wrote?" He suggested that by reading between the lines, one could discern the clues that this was in fact an invitation to participate in a ghostwriting venture.

All of this is sort of fun and entertaining, but in my opinion it is not the heart of the matter. To fully understand what is going on here you have to know psychiatry the way an expert like Dr. Carlat does (and admittedly I certainly do not). You have to know that BlueSpark has a contract with Sanofi-Aventis and that they are makers of a "brand new" antidepressant, which is really nothing more than a once-a-day version of an old standby generic antidepressant, bupropion. You need to know that bupropion is indeed well regarded as a useful and effective antidepressant, but that the older generic forms are dirt cheap compared to the nearly incredible price tag of this new drug form (would you believe $5.58 a dose, compared to 28 cents for the generic?). For this extra price you get exactly one benefit--if you need to take the highest daily dose of bupropion, instead of having to take two pills once a day, you can now take one pill once a day.

So the really critical point is this (from Dr. Carlat): "[L]et’s face it. No psychiatrist is going to wake up in the morning and say, 'I think today is the day I’ll work on a review article on bupropion and depression and how awful it is that the tiny number of patients who require the maximum dose have to take two pills in the morning instead of one. Yes—this will be a significant contribution to the medical literature.' This would never happen, because there’s nothing new or interesting in this topic. We know that bupropion works well for depression, and we’ve known it even since it was approved by the FDA in 1985.No, the only reason a psychiatrist would get motivated to write such an article is if a cold-call email solicitation from BlueSpark gets pas[t] the spam filter. I’m guessing that BlueSpark hopes that eventually they will find an uncreative, mid-level academic who is treading water professionally, and who will jump at the chance to pocket a little extra money while simultaneously padding the resume with a publication that will require essentially no work to produce. ...Whether or not this meets the formal definition of ghost-writing, it is clearly a manipulation of the medical literature, a kind of plastic surgery of science. The articles may look impressive, and they may look real, but in fact they will be phony."